Blunted opioid regulation of the HPA stress response during nicotine withdrawal: therapeutic implications

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Endogenous opioids regulate pain, drug reward, and stress responses. We have previously shown reduced hypothalamic-pituitary-adrenal (HPA) responses to psychological stress and to opioid blockade among dependent smokers. In this study, we examined the extent to which biologically confirmed nicotine withdrawal alters endogenous opioid regulation of HPA axis functioning during rest and in response to acute stress. Smokers were randomly assigned to one of two conditions; 24 h withdrawal from all nicotine-containing products (n = 62) or smoking ad libitum (n = 44). A nonsmoking comparison group (n = 43) was also included. Participants (85 males and 64 females) completed two acute stress sessions during which a placebo or 50 mg of naltrexone (opioid antagonist) were administered using a double-blind design. Blood and saliva samples (assayed for cortisol and adrenocorticotropic hormone, i.e. ACTH) and mood measures were obtained during a resting absorption period, after acute stress (public speaking, mental arithmetic, and cold pressor tasks), and during an extended recovery period. Results indicated that opioid blockade (naltrexone) was associated with increased ACTH and cortisol responses to stress, and tobacco withdrawal was associated with blunted hormonal responses. A pattern of sex differences also emerged, with women exhibiting reduced ACTH responses to stress and higher ACTH and plasma cortisol responses to opioid blockade. These results indicated that compared to ad libitum smoking, nicotine withdrawal is associated with blunted opioid modulation of the HPA axis. Sex may modulate these effects. Blunted endogenous opioid regulation may underlie an incentive process that reinforces smoking behavior and may warrant therapeutic attention.

Original languageEnglish (US)
Pages (from-to)529-540
Number of pages12
Issue number5
Early online dateSep 30 2020
StatePublished - Sep 30 2020

Bibliographical note

Funding Information:
This research was supported in part by grants to the first author from the Error! Hyperlink reference not valid. [R01DA016351 and R01DA027232]. We would like to thank the following individuals for their help with collecting (Barbara Gay, Elizabeth Ford, Dayna Schleppenbach, Soni Rraklli Uccellini, Angie Forsberg) and managing (Jie Gooder) the data for this study. Nikki Neumann, Christopher Schweiger, and Dan Vuicich helped with the conducting the assays.

Publisher Copyright:
© 2020 Informa UK Limited, trading as Taylor & Francis Group.


  • Endogenous opioid function
  • HPA
  • addiction
  • nicotine withdrawal
  • stress


Dive into the research topics of 'Blunted opioid regulation of the HPA stress response during nicotine withdrawal: therapeutic implications'. Together they form a unique fingerprint.

Cite this